1-alkenyl-3-alkyl-5-sulfonamido-6-aminouracil



UnitedStates Patent l-ALKENYL-3-ALKYL-5-SULFONAMIDO-6- AMINOURACIL MaxJ. Kalm, Skokie, Ill., assignor to G. D. Searle & Co., Chicago, 111., acorporation of Delaware No Drawing. Application December 27, 1957 SerialNo. 705,509

6 Claims. (Cl. 260-2565) This invention relates to1-alkenyl-3-alkyl-5-sulfonamido-G-aminouracils and processes for themanufacture thereof. More particularly, this invention relates to theCompounds of the formula wherein R is an alkenylradical, R is an alkylradical, and R is an alkyl or aryl radical.

The alkenyl radicals comprehended by R in the foregoing formula includevinyl, allyl, butenyl, methylallyl, and like univalent groupings derivedby elimination'of a single hydrogen atom from acyclic hydrocarbonscomprising fewer than 9 carbon atoms and containing a double bond. Thealkyl radicals designated by the R and R in the formula are desirablylower alkyl radicals, to wit, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, tert.-pentyl,hexyl, isohexyl, heptyl, octyl, and in general, G i-I groupings whereinn is a positive integer amounting to less than 9. The aryl radicals towhich R" alternatively refers are such as phenyl and tolyl groupings.

The compounds of this invention are useful because of their valuable andselective pharmacological activity. They appear to inhibit the appetitewithout producing pressor-depressor, diuretic, or other .responses whichwould complicate their administration to the animal organism.

Manufacture of the subject composition proceeds by heating anappropriate 5,6-diaminouracil i N HzN O Hm i N- R H and sulfonylchloride RSO Cl together in the presence of a basic catalyst such aspyridine, the meanings of R, R, and R" being as previously defined.Where the starting diaminouracil is not commerically available, it canbe synthesized from the corresponding compound lacking the S-aminoconstituent by reaction thereof with aqueous sodium nitrite, and reduction of the resultant nitroso compound with sodium hydrosulfite inaqueous ammonia.

The following examples describe in detail certain of the uracilsillustrative of the present invention and methods which have beendevised for their preparation. However, the invention is not to beconstrued as limited thereby, either in spirit or in scope, since itwill be apparent to those skilled in the art of organic synthesis that Imany modifications, both of materials and of methods,

may be practiced without departing from the purpose and intent of thisdisclosure. In the examples hereinafter detailed, temperatures are givenin degrees centigrade C.) and relative amounts of materials in parts byweight, except as otherwise noted.

Example 1 A. 5 ,6-diamin0-3-methyl-1 -(2-methylallyl uraciL-To asolution of 195 parts of 6-amino-3-ethyl-1-(Z-methylallyl)uracil and 69parts of sodium nitrite in 1375 parts of water at 8590 C. is added, withagitation, a solutionof 65 parts of glacial acetic acid in 195 parts ofwater. The reaction mixture is maintained in the prescribed of which isl48153 C. (corrected).

B. 6-amin0-5-ezhylsulfonamido-3-methyl-1-(2-methylallyl) uracil.-To asolution 'of 25 parts of 5,6-diamino-3- methyl-l-(2-methylallyl)uracilin 250 parts of pyridine is cautiously added 15 parts ofethanesulfonylchloride. The resultant mixture is heated, with agitation,at the boiling point of the solvent under reflux for 1% hours, whereuponthe pyridine is removed by evaporation at reduced pressures and 250parts of water added to the residue. Crystallization occurs.Recrystallization from alcohol affords pure, white6-amino-5-ethylsulfonamido- 3-methyl-1-(Z-methylallyl)uracil, themelting point of which is 157-161 C. (corrected). The product has theformula mcrsorg k Example 2 A. 1-allyl-5,6-diamino-3-ethyIuraciL-To asolution of 213 parts of 1-allyl-6-amino-3-ethyluracil monohydrate and69 parts of sodium nitrite in 1370 parts of water at -90 C. is added,with agitation, a solution of 65 parts of glacial acetic acid in partsof water. The reaction mixture is maintained in the prescribedtemperature range for 30 minutes, then chilled to 20 C. The brightpurple nitroso compound precipitated is removed by filtration and washedwith water. To a suspension of this material in 1350 parts of water isadded 205 parts of concentrated ammonium hydroxide. The resultantsolution is heated to 45 C., whereupon sufiicient sodium hydrosulfite isintroduced--portionwise-to discharge the orange-red color, while thetemperature rises to 85 C. The yellow solution is filtered, hot. Thefiltrate is cooled and extracted with chloroform. The chloroform extractis dried over anhydrous sodium sulfate and then stripped of solvent byevaporation at reduced pressures. The crystalline residue,recrystallized from ethyl acetate, melts at 138.5-141.5 C. (corrected).This material is l-allyl- 5,6-diamino-3-ethyluracil.

B. 1-allyl-6-aminn-3-ethyl-S-heptylsulfonamia'ouracil. Using thetechnique of Example 1B, 25 parts of l-allyl- To a sus-'5,6-diamino-3-ethyluracil and 24 parts of heptanesulfonyl chloride arecaused to react in 250 parts of pyridine. Work up as in the examplecited affords l-allyl-6-amino- 3-ethyl-5-heptylsulfonamidouracil, of theformula Example 36-amin0-3-methyI-I-(2-methylallyl)5-phenylsulfonamidouraciL-Interactionbetween 25 parts of 5,6-diamino- 3-methyl-1-( 2-methylallyl)uracil and21 parts of benzenesulfonyl chloride in 250 parts of pyridine accordingto the technique of Example 1B affords 6-amino-3-methyl-1-(2-methylallyl)-5-phenylsulfonamidouracil. After tworecrystallizations from anhydrous alcohol, the product melts atapproximately 196197.5 C. (corrected). It has the formula a Example 46-amino-3-methyl-1-(Z-methylallyl)--p-t0lylsulfonamid0uracil.-Approximately 25 parts of5,6-diamino-3-ethyl- 1-(2-methylallyl)uracil and 23 parts of p-toluenesulfonyl chloride are heated together in 250 parts of pyridine1-allyl-6-amino-3-ethyl-5-phenylsulfonamidoura- 4 according to theprocedures set forth in Example 18. Work up as there described aflFords,after two crystallizations from anhydrous alcohol, pure, white6-amino-3- methyl-l-(2-methylallyl)-5-p-tolylsulfonamidouracil, themelting point of which is 199-200" C. (corrected). This material has theformula mo-Q-sm-rr Example 6 1-allyl-6-amin0-3-ethyl 5p-tolylsulfonamid0uracil.-- Using the technique of Example 1B, 25 partsof l-allyl- 5,6-diamino-3-ethyluracil and 23 parts of p-toluenesulfonylchloride are reacted together in 250 parts of pyridine to produce1-allyl-6-amino-3-ethyl-S-p-tolylsulfonamidouracil, which,recrystallized from anhydrous alcohol,

melts at 200.5-202.5 C. (corrected). The product has the formula What isclaimed is: 1. A compound of the formula wherein R is selected from thegroup consisting of allyl and methylallyl radicals; R is a lower alkylradical; and

5 R" is selected from the group consisting of lower alkyl,

phenyl, and tolyl radicals.

2. 6-arnino-5-ethylsulfonamido-3-methyl-1 (Z-methylallyl)uracil.

3. 6-amino-3-methyl-1-(Z-methylallyl)-5-phenylsulfonamidouracil.

4. 1-allyl-6-amino-3-ethyl-5-phenylsulfonamidouracil.

5. 6-amino-3-methyl-l-(2-methylallyl)-5- p-tolylsulfonamidouracil.

6. 1-allyl-6-amino-3-ethyl-5-p-tolylsulfonamidouracil.

References Cited in the file of this patent Bredereck et al.: ChemischeBerichte, vol. 86, pp. 850- 856 (1953).

, UNITED STATES PATENT- (TF FICE' CERTIFICATE" OF CORRECTION Patent No.2,931,613 v April 5, 1960 I Max J. Kalm I i It is hereb; certified thaterror appears in the printed speoification of the above numbered patentrequiring correction and that the said Letters Patent should read ascorreoted below.

Colomn 1, lines 19 to 25, the formula should appear as shown belowinstead of as in the patent;

line 58", the formula should appear as shown below instead of as in thepatent:v

R SQ C].

Signed and sealed this 13th day of September 1960 (SEAL) Attestz' KARLH. AXLINE- ROBERT C. WATSON Attesting Officer Commissioner of Patents

1. A COMPOUND OF THE FORMULA